Biliary clearance of erythritol is being widely used as an estimate of canalicular bile flow although review of the data upon which this use is based indicates that the data are both sparse and indirect. The validity of using erythritol clearance will be assessed more extensively in a series of indirect studies carried out in experimental animals. A direct assessment of duct permeability and function will be initiated. Basically, a major effort will be made to establish the techniques of microdissection and microperfusion of the biliary duct system as a means of directly assessing duct functions. Recent observations in our laboratory have provided evidence that the mechanism by which bile salts enhance BSP excretion involves a direct bile salt effect rather than an increase in bile salt mediated bile flow. This has led us to examine the possibility of interaction of BSP compounds with bile salts. Initial observations strongly suggest that such an interaction does occur. We plan to examine by a variety of in vitro techniques the mechanism of interaction of BSP molecules with various bile salts and bile salt analogues and to correlate these findings with in vivo observations of the effects of these bile salts and bile salt analogues on BSP excretion. We have devoted a considerable effort to an examination of the importance of conjugation for hepatic transport of compounds into bile. We have developed synthetic and analytical techniques that permitted an appraisal of the importance of conjugation for BSP transport in guinea pigs, rats and dogs. We now plan to extend these observations by examining the importance of conjugation for transport of a variety of compounds excreted as glucuronides. Finally, further assessment of mechanisms that control the bile acid independent fraction of canalicular bile flow will be carried out. It seems probable that depression of this fraction of bile flow is linked to the development of cholestasis. BIBLIOGRAPHIC REFERENCES: Whelan, G. and B. Combes: Phenobarbital-enhanced biliary excretion of administered unconjugated and conjugated sulfobromophthalein (BSP) in the rat. Biochem. Pharmacol. 24:1283, 1975.